Key Points

In patients with locally advanced or metastatic urothelial carcinoma after failure of platinum-based therapy, avelumab produced an objective response in 17% of patients with at least 6 months of follow-up.

The estimated proportion of responses lasting > 24 weeks was 96%.

As reported in The Lancet Oncology by Patel et al, the anti–programmed cell death ligand 1 (PD-L1) antibody avelumab (Bavencio) produced durable responses in patients with locally advanced or metastatic urothelial carcinoma after failure of platinum-based therapy in two expansion cohorts of the phase I dose-expansion JAVELIN Solid Tumor study. These findings supported the recent approval of avelumab in this setting.

Study Details

The pooled analysis of 2 expansion cohorts from the study involved 249 patients unselected for PD-L1 expression from 80 sites in the United States, Europe, and Asia enrolled between September 2014 and March 2016. Of them, seven were cisplatin-ineligible and had never received platinum-based treatment; these patients were excluded from the efficacy analysis. Patients had to have a life expectancy of at least 3 months and at least one measurable lesion.

Treatment consisted of avelumab at 10 mg/kg via 1-hour intravenous infusion every 2 weeks until disease progression, unacceptable toxicity, or other reason for withdrawal. The primary endpoint was confirmed best overall response on Response Evaluation Criteria in Solid Tumor version 1.1 on independent review. Efficacy and safety data were evaluated at data cutoff in June 2016.

Among all patients: the median age was 68 years (69% aged ≥ 65 years); 72% were male; 70% were from the United States, 25% from Europe, and 5% from Asia; 78% were white and 7% Asian; all had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (35%) or 1 (65%); 77% had lower tract disease; 84% had visceral metastases; 81% had hemoglobin levels ≥ 100 g/L; 79% had albumin levels ≥ 35g/L; 65% were ever smokers; 29% had received two and 21% at least three prior treatments for advanced disease; PD-L1 expression status was positive (≥ 5%) in 33% and negative in 50%; and the Bellmunt risk score was 0 in 23%, 1 in 46%, 2 in 24%, and 3 in 7%.

Response Rates

The median duration of avelumab treatment at the time of analysis was 12 weeks, and the median follow-up was 9.9 months. Among 161 postplatinum patients with ≥ 6 months of follow-up, complete (9 patients, 6%) or partial response (18 patients, 11%) was observed in 27 patients (17%). Stable disease was observed in an additional 23% of patients. Complete response, partial response, and stable disease rates were 10%, 14%, and 29% among PD-L1–positive patients and 3%, 11%, and 20% among PD-L1–negative patients, respectively.

The median time to response was 11.4 weeks. The median duration of response was not reached at data cutoff; the estimated proportion of responses lasting ≥ 24 weeks was 96%. Median progression-free survival was 6.3 weeks, with 23% of patients progression-free at 6 months. Median overall survival was 6.5 months, and 6-month overall survival was 53%.

The most common treatment-related adverse events of any grade were infusion-related reaction (29%, all grade 1 or 2), fatigue (16%), and rash (14%). Grade ≥ 3 treatment-related adverse events occurred in 8% of patients, with the most common being fatigue (2%) and asthenia, elevated lipase, hypophosphatemia, and pneumonitis (1% each). Treatment-related serious adverse events occurred in 8%, including infusion-related reaction, diarrhea, and pneumonitis in at least one patient each. Immune-related adverse events occurred in 14% of patients, including rash (10%) and hypothyroidism (4%).

Avelumab was permanently discontinued due to treatment-related adverse events in 6% of patients. One patient died due to a treatment-related adverse event (pneumonitis).

The investigators concluded: “Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma, and it has received accelerated [U.S. Food and Drug Administration] approval in this setting on this basis.”